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Differential Activation of Insulin Receptor Isoforms by Insulin-Like Growth Factors Is Determined by the C Domain

School of Molecular and Biomedical Science (A.D., G.V.B., G.W.B., J.C.W., B.E.F.), The University of Adelaide, Adelaide 5005, Australia; Commonwealth Scientific and Industrial Research Organisation Division of Molecular and Health Technologies (A.D., G.V.B., L.J.C.), Adelaide 5000, Australia; and Department of Pediatrics (J.M.C., A.L., C.T.R.), Oregon Health and Science University, Portland, Oregon 97239

Address all correspondence to: Charles T. Roberts, Jr., Ph.D., Department of Pediatrics (NRC-5), Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239. E-mail robertsc{at}ohsu.edu.

The actions of IGF-I and IGF-II are thought to be largely due to their activation of the IGF-I receptor. However, IGF-II can also bind with high affinity to, and effectively activate, an isoform of the insulin receptor (IR-A) that lacks a sequence at the carboxyl-terminal end of the extracellular subunit due to the alternative splicing of exon 11. This isoform is poorly activated by IGF-I. Here, we show that IGF-II, but not IGF-I, induces potent autophosphorylation of residues Y1158, Y1162, and Y1163 in the activation loop of the kinase domain and tyrosine 960 in the juxtamembrane region of both IR-A and IR-B (exon 11+) isoforms. We have also found, by using IGF chimeras, that the C domain of IGF-II completely accounts for the ability of IGF-II to stimulate IR autophosphorylation compared with IGF-I. We further show that the C domains are responsible for the differential abilities of IGF-II and IGF-I to activate phosphorylation of insulin receptor substrate-1 and Akt, as well as their ability to induce migration and cell survival via the IR-A. Finally, we show for the first time that IGF signaling through the IR-A can protect cells from butyrate-induced apoptosis. In summary, our studies define the structural determinants that allow potent IGF-II signaling and regulation of cellular functions through the IR-A and provide novel insights into IGF signaling via the IR.

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